REVIEW www.nature.com/clinicalpractice/endmet Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates Diva D De León and Charles A Stanley* SUMMARY INTRODUCTION Etiology of neonatal hypoglycemia Hyperinsulinism is the single most common mechanism of hypoglycemia Hypoglycemia is a frequent problem in newborn in neonates. Dysregulated insulin secretion is responsible for the infants that must be diagnosed and treated effi- transient and prolonged forms of neonatal hypoglycemia, and congenital ciently to avoid seizures and permanent brain genetic disorders of insulin regulation represent the most common damage. Management is complicated by the fact of the permanent disorders of hypoglycemia. Mutations in at least five genes have been associated with congenital hyperinsulinism: they that neonates present a remarkably wide range of encode glucokinase, glutamate dehydrogenase, the mitochondrial possible causes for hypoglycemia. These include enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase, and the two transient forms of hypoglycemia that can occur components (sulfonylurea receptor 1 and potassium inward rectifying in normal infants, more prolonged forms of channel, subfamily J, member 11) of the ATP-sensitive potassium hypoglycemia that are associated with compli- channels (K channels). K hyperinsulinism is the most common and cations of gestation and delivery, and neonatal ATP ATP presentation of permanent hypo glycemia severe form of congenital hyperinsulinism. Infants suffering from KATP hyperinsulinism present shortly after birth with severe and persistent dis orders due to endocrine or metabolic diseases hypoglycemia, and the majority are unresponsive to medical therapy, thus (Box 1). The risks of these various forms change requiring pancreatectomy. In up to 40–60% of the children with KATP hyperinsulinism, the defect is limited to a focal lesion in the pancreas. dramatically over the first few days after birth. In these children, local resection results in cure with avoidance of the For example, it has been known for over complications inherent to a near-total pancreatectomy. Hyperinsulinism 30 years that up to 50% of normal neonates can also be part of other disorders such as Beckwith–Wiedemann are unable to maintain plasma glucose above syndrome and congenital disorders of glycosylation. The diagnosis and 50 mg/dl with fasting for as little as 8 h after management of children with congenital hyperinsulinism requires a delivery.1 The high risk of hypoglycemia in multidisciplinary approach to achieve the goal of therapy: prevention of normal neonates reflects incomplete develop- permanent brain damage due to recurrent hypoglycemia. ment at birth of the pathways for hepatic KEYWORDS ATP-sensitive potassium channels, glucokinase, gluconeogenesis and ketogenesis. These path- glutamate dehydrogenase, hyperinsulinism, hypoglycemia ways quickly mature and by 2–3 days of life, the susceptibility of normal infants to hypo- REVIEW CRITERIA glycemia resolves. Maternal diabetes or medi- We searched for original articles focusing on hyperinsulinism in PubMed between 1970 and 2006. The search terms we used were “hypoglycemia”, cations may be important contributors to the risk of hypoglycemia during the first few days “hyperinsulinism”, “KATP channels”, “glucokinase”, “glutamate dehydrogenase”, and “short chain 3-hydroxyacyl-CoA dehydrogenase”. All papers identified after delivery. Peripartum complications, such were English-language full text papers. We also searched the references lists of as birth asphyxia or other perinatal stresses, can identified articles for further papers. be associated with prolonged hypoglycemia that persists for several weeks after birth. DD De León is an Assistant Professor of Pediatrics, and CA Stanley is a As shown in Box 1, with the exception of the Professor of Pediatrics, at the University of Pennsylvania, Philadelphia, PA, normal immaturity of fasting adaptation, which USA; DD De León is an Attending Physician in, and CA Stanley Chief of, the accounts for the high risk of hypoglycemia Division of Endocrinology, The Children’s Hospital of Philadelphia. in the first 12 h, hyper insulinism is the single most common of the transient and permanent Correspondence *Division of Pediatric Endocrinology, The Children’s Hospital of Philadelphia, Abramson Research dis orders of hypo glycemia. This Review will there- Center, Room 802, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA fore focus on our current understanding of the [email protected] various forms of hyperinsulinism in the newborn and their diagnosis and management. Particular Received 13 February 2006 Accepted 25 August 2006 www.nature.com/clinicalpractice emphasis is placed on the genetic dis orders doi:10.1038/ncpendmet0368 associated with congenital hyper insulinism and JANUARY 2007 VOL 3 NO 1 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 57 nncpendmet_2005_084.inddcpendmet_2005_084.indd 5577 11/12/06/12/06 22:41:47:41:47 ppmm REVIEW www.nature.com/clinicalpractice/endmet 2 Box 1 The etiology of hypoglycemia in neonates. First described in 1954 by MacQuarrie as “idiopathic hypoglycemia of infancy”, CHI has Transient neonatal hypoglycemia been referred to by a large number of terms, Day 1 of life: developmental immaturity of fasting adaptation (mechanism: impaired ketogenesis and including nesidioblastosis, leucine-sensitive gluconeogenesis) hypoglycemia, islet dysregulation syndrome, First 2 days of life: transient hypoglycemia due to and persistent hyperinsulinemic hypoglycemia maternal factors of infancy. We prefer to denote the condition ■ maternal diabetes (mechanism: hyperinsulinism) as hyperinsulinism for simplicity and to avoid ■ intravenous glucose administration during labor confusion, and to refer to the group of permanent and delivery (mechanism: hyperinsulinism) inborn conditions as CHI. ■ medications: oral hypoglycemics, terbutaline, Worldwide, CHI occurs at a frequency of propranolol (mechanism: hyperinsulinism) 1 in 30,000 to 1 in 50,000 live births,3 but in Prolonged neonatal hypoglycemia some isolated populations rates of 1 in 3,200 Perinatal stress-induced hyperinsulinism (low birth have been reported.4 Higher rates of 1 in 2,500 weight, birth asphyxia, maternal toxemia or live births have been reported in areas of high pre-eclampsia, prematurity) consanguinity such as the Arabian Peninsula.5 Beckwith–Wiedemann syndrome Hypopituitarism MOLECULAR BASIS OF CONGENITAL Permanent neonatal hypoglycemia (caused by HYPERINSULINISM congenital endocrine or metabolic disorders) Mutations in five proteins have been associated Congenital hyperinsulinism with CHI: the sulfonylurea receptor 1 (SUR-1, ■ ATP-sensitive potassium channel a member of the superfamily of ATP-binding hyperinsulinism ■ glutamate dehydrogenase hyperinsulinism cassette proteins, encoded by ABCC8 [ATP- 5 ■ glucokinase hyperinsulinism binding cassette subfamily C, member 8]); ■ short-chain 3-hydroxyacyl-CoA dehydrogenase Kir6.2 (encoded by KCNJ11 [potassium inward hyperinsulinism rectifying channel, subfamily J, member 11]);6 ■ congenital disorders of glycosylation glucokinase (encoded by GCK);7 glutamate Counter-regulatory hormone deficiency de hydrogenase (GDH; encoded by GLUD-1 ■ hypopituitarism [glutamate dehydrogenase 1]);8 and the mito- ■ adrenal insufficiency chondrial enzyme short-chain 3-hydroxyacyl-CoA Gluconeogenesis or glycogenolysis enzyme defects dehydrogenase (SCHAD; encoded by HADH Fatty acid oxidation disorders [hydroxyacyl-coenzyme A de hydrogenase]; formerly HADHSC).9 SUR-1 and Kir6.2 combine to form the β-cell ATP-sensitive potassium the very common, but as yet poorly understood, channel (KATP channel). Table 1 summarizes the prolonged hyperinsulinism associated with major features of these disorders. perinatal stresses. Other well-known risk factors for neonatal hypoglycemia, such as maternal ATP-sensitive potassium channel diabetes or hypoglycemic medications, will not congenital hyperinsulinism be addressed. Pathophysiology Loss-of-function mutations in the KATP channel Congenital hyperinsulinism result in KATP channel hyperinsulinism (KATP- Congenital hyperinsulinism (CHI) represents HI)—the most common and severe form of CHI. a group of clinically, genetically, and morpho- The β-cell KATP channel is a hetero-octameric logically heterogeneous disorders characterized complex comprising two subunits: a K+-selective by dysregulated insulin secretion and resulting in pore-forming subunit, Kir6.2, and a regulatory severe and persistent hypoglycemia. During the subunit, SUR-1. Four Kir6.2 subunits form the last 10 years, advances in molecular genetics and central pore, coupled to four SUR-1 subunits. in the understanding of β-cell biochemical path- The KATP channel is inhibited by sulfonylurea ways have resulted in the understanding of the drugs (used therapeutically to stimulate insulin pathophysiology of most forms of CHI. Despite secretion in type 2 diabetes) and activated by these advances, treatment of the infant with CHI diazoxide (the main medical treatment for continues to be one of the major challenges in CHI). The KATP channels couple the energy state pediatric endocrinology. of the β-cell to membrane potential by sensing 58 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM DE LEÓN AND STANLEY JANUARY 2007 VOL 3 NO 1 nncpendmet_2005_084.inddcpendmet_2005_084.indd 5588 11/12/06/12/06 22:41:50:41:50 ppmm REVIEW www.nature.com/clinicalpractice/endmet Table 1 Classification of genetic forms